Myocardial infarction contributes a major reason for cardiovascular disease despite the multiple significant therapeutic advances. Myocardial ischemia/reperfusion injury is still a major unsolved problem. Histone acetyltransferases (HAT) and histone deacetylases (HDAC) are enzymes that modify the expression of genes by regulating chromatin structure. They also target non-histone protein and represent a general regulatory mechanism in biological signaling. HDAC inhibitors have shown efficacy as anti-cancer drugs and are emerging as exciting clinical treatments targeting solid and hematological malignancies. HDAC inhibition blunts cardiac hypertrophy. Our studies have shown that HDAC inhibition is associated with cardioprotection in acute myocardial ischemia and myocardial infarction in mouse. HDAC inhibition results in the acetylation and activation of both p38 and MKK3 in mouse hearts. We have identified that p38 is acetylated at lysine 53 and lysine 121 sites. We also demonstrated that HDAC inhibition resulted in an increase in c-kit stem cells, cell proliferation and mitosis in chronic infarcted hearts. However, the mechanism(s) by which HDAC inhibition protects the heart against injury remain unknown. Our working hypothesis is that HDAC inhibition protects the heart against myocardial injury through the activation of MKK3 and p38. We further hypothesize that the protection of HDAC inhibition is related to prevention of myocardial remodeling and an increase in newly formed cardiac components following myocardial infarction. Utilizing genetic and physiological approaches, we will test: Specific Aim 1: Examine HDAC activity and HDAC 3, 4 and 5 in acute myocardial ischemia, ischemia/reperfusion and chronic myocardial infarction: We will measure HDAC activity in ischemic myocardium in both acute ischemia, ischemia/reperfusion and chronic myocardial infarction. We will examine HDAC 3, 4 and 5 proteins and their subcellular distributions in both settings above. Specific Aim 2: Assess the roles of MKK3, p38 and Akt1 signaling pathway in the cardioprotection induced by HDAC inhibition: Using mice with deletion of MKK3, the upstream activator of p38, elimination of cardiac p38 and pharmacologic inhibition of p38, we will determine whether inhibition of MKK3 and p38 will abrogate the cardioprotective effect(s) of HDAC inhibition. Specific Aim 3: Decipher the molecular mechanism (s) of p38 activation using in vitro analysis and cell culture models: Using established the in vitro and cell culture model, we will characterize the acetylation of p38 and that such a post-translational modification will regulate p38 activity. Specific Aim 4: Explore whether HDAC inhibition is associated with myocardial repair following chronic myocardial infarction. Investigating the role of HDAC inhibition in ischemic heart could provide not only new insight into our understanding of cardiovascular biology but also development of therapeutic strategies for patients with ischemic heart disease and other cardiovascular disorders. PUBLIC HEALTH RELEVANCE: This project not only provides a new insight into our understand a novel mechanism by which HDAC inhibition protects ischemic heart, but it also holds promise to develop a therapeutic strategy for patients with ischemic heart diseases and other cardiovascular disorders.